1. Field of the Invention
The present device relates to apparatus and methods for use in controlling the temperature of edge vials in a freeze drying process to enable analysis, development, and optimization of freeze drying protocols with a minimum amount of sample required to develop such protocols.
2. Description of Background Art
Problem: During the primary drying phase of a freeze drying process, edge vials, those which are not surrounded by 6 other vials, will sublimate faster than centers vials, those vials which are surrounded by 6 other vials. The ‘edge vial effect’ creates two problems:                a. First, in large batches the non-uniformity of edge vials during primary drying result in lower process yields, increased drying times to keep the edge vials below their critical temperature, and inconsistent product quality.        b. Second, when attempting to freeze dry a small batch of product there is a greater percentage of edge vials and the small batch dries significantly faster than a large batch. The result is that a small batch cannot be used to develop freeze drying protocols. Using large batches costs more in product, time, and resources.        
The need for an apparatus to eliminate the ‘edge vial effect’ is apparent.
A solution to this problem would have benefits which include but are not limited to:                a. First, in large batches the non-uniformity of primary drying would be eliminated resulting in better yields and more consistent quality and shorter primary drying times.        b. Second, an apparatus would enable a method to use a small batch of product for analyzing and developing freeze drying protocols. This will save significant time, money and resources for the user.        
Overview—The freeze drying process is a dynamic heat and mass transfer process that is typically controlled by adjusting the shelf temperature at a given vacuum level over a period of time. The shelf temperature profile is a sequence of discrete steps for the three main processes; freezing, primary drying and secondary drying.
A freeze drying recipe, protocol, or profile that works on one freeze dryer may not work on other freeze dryers due to differences in the heat transfer dynamics inherent to each. Therefore, developing a protocol that can be easily transferred between freeze dryers often requires extensive testing and each profile may need to be modified many times to produce the same, or at least similar, process results.
Currently, the development of freeze drying protocols is done in a rudimentary manner, using a significant amount of product in a larger than necessary freeze dryer, with multiple runs being performed to gather the required data. This iterative process is time intensive and requires an ample amount of product, which can be expensive. A sufficient amount of product may not be available to use this method of protocol development.
The freeze drying process has two major steps: freezing and drying. Each step involves a different heat transfer dynamic between the shelf of the freeze dryer and the product, depending on the number of vials containing the product and the characteristics of the freeze dryer. Freezing is a cooling process with the heat transfer from the product to the shelf at atmospheric pressure. Drying is a heating process wherein heat is added from the shelf to the product while under a vacuum which causes the ice to sublimate.
The heat transfer dynamics of freeze drying are directly affected by the type and quantity of vials and the freeze drying equipment. Creating the right freezing process and primary drying process is critical to developing a robust and efficient freeze drying cycle. It is well understood that a small nest of, for example 1 to 37, vials will freeze faster and sublimate much faster than a full shelf of vials (typically containing 100 to 2000 vials) when processed with the same freeze drying protocol. Larger batches of vials dry more slowly due to reduced radiation effects and cooling from inter-vial heat transfer dynamics. Smaller batches of product have a larger radiation heat transfer component and have a minimal inter-vial cooling effect allowing more of the energy to be transferred into the sublimation process which reduces the drying time and produces different final product results. This has made the creation of freeze drying protocol development with a small batch of vials extremely difficult and mostly impractical up to this point in time.
The concept for developing protocols is to establish meaningful freezing and primary drying profiles in a Source Freeze Dryer (“SFD”) using a small batch that is intended to mimic the characteristics and conditions of larger batches that are used in production, which is the Target Freeze Dryer (“TFD”). While mimicking the TFD as closely as possible, critical process parameters can be monitored and/or controlled, and used to develop a transferrable freeze drying protocol.
Freezing—
Proper freezing is required to improve the sublimation process and to protect the product. Achieving the proper size and consistency of the ice crystals are critical to creating good product. Larger ice crystals as well as intra-vial consistency enables more efficient primary drying. Some products may also exhibit unwanted changes in pH, precipitation, or phase separation if not properly frozen.
Freezing, in the freeze drying process occurs in several discrete steps. The process consists of super-cooling the liquid, nucleation where 3-19% of the water is crystalized, the growth of the ice crystal structure in the minimal freeze concentrate until all the water is frozen and finally the solidification of the maximal freeze concentrate to a temperature below the glass transition temperature. Proper crystal structure, which typically comprises high porosity, enables more efficient primary drying and helps produce a visually appealing cake and may aid in reducing reconstitution time. At times an annealing step, which involves holding the product at a temperature above the final freezing temperature for a certain period of time, may be added to encourage crystallization of the excipients and to allow the ice crystals to increase in size prior to primary drying.
Nucleation—
In typical applications, a freezing protocol is used which reduces the shelf temperature at a specified rate and holds the shelf temperature for a period of time to ensure the product is frozen and stable. When cooling the shelves at a programmed rate, nucleation occurs in an undesirably random fashion resulting in inconsistent crystallization across a batch which results in extended primary drying times and inconsistent product results.
During the freezing process energy is removed from the vials by cooling the shelf surface. The product temperature cools below its freezing point (super-cools) until there is a nucleation event in one of the vials. The nucleation event is an exothermic event which raises the temperature of the product and vial to near 0 C. In a closely packed array of vials, the nucleating vial prevents adjacent vials from nucleating by adding releasing heat and increasing their temperature. Before the adjacent vials can nucleate, the nucleating vial must complete the ice crystallization process and reduce in temperature. Once the available water in the product is crystalized and the exothermic reaction energy is reduced, another adjacent vial can nucleate. This process results in vials nucleating at differing temperature and rates, which produces differing ice structures in the vials. The result is a primary drying cycle that can only sublimate at the rate of the vial with the least favorable ice crystal structure, and therefore a longer than necessary primary drying cycle is necessary. When a small batch of product is used, the vials will nucleate and freeze faster resulting in a crystal much different than a large batch and therefore will produce different results.
To produce a more consistent crystal structure across the batch a method of controlled or forced nucleation can be applied wherein the liquid product is super-cooled to a predetermined temperature and then an activation event is created which forces the nucleation process. Typically, all vials nucleate at the same time, temperature, and rate which results in very uniform initial crystal structure across the batch. For more consistent intra-vial crystal structure a method for controlling heat flow may be added after controlled nucleation occurs.
If controlled nucleation is performed, only a fraction of the available water crystalizes, and the majority of crystal growth occurs post-nucleation. Controlling the heat flow after nucleation is critical to produce a more uniform intra-vial crystal structure, enabling shorter primary drying times and improving product consistency and quality.
During the freezing process energy is removed from the vials by cooling the shelf surface. The product temperature cools below its freezing point (super-cools) until there is a nucleation event in one of the vials. The nucleation event is an exothermic event which raises the temperature of the product and vial to near 0 C. In a closely packed array of vials, the nucleating vial prevents adjacent vials from nucleating by adding releasing heat and increasing their temperature. Before the adjacent vials can nucleate, the nucleating vial must complete the ice crystallization process and reduce in temperature. Once the available water in the product is crystalized and the exothermic reaction energy is reduced, another adjacent vial can nucleate. This process results in vials nucleating at differing temperature and rates, which produces differing ice structures in the vials. The result is a primary drying cycle that can only sublimate at the rate of the vial with the least favorable ice crystal structure, and therefore a longer than necessary primary drying cycle is necessary. When a small batch of product is used, the vials will nucleate and freeze faster resulting in a crystal much different than a large batch and therefore will produce different results.
Drying—
Once the product is frozen, the pressure in the chamber is reduced and primary drying may begin. Drying can be further divided into primary drying and secondary drying steps. Primary drying is a sublimation process where ice in a frozen product turns directly into vapor which is then condensed on a cold condensing surface leaving behind a matrix of concentrated product in the vial or tray on the shelf. Secondary drying is a desorption process; the remaining moisture in the concentrated product matrix is reduced to a level that is best for the product's long term stability.
Freeze drying requires a process to efficiently remove water without losing the product matrix structure created during the freezing step. The key to an optimized drying cycle is keeping the product at a temperature slightly below its critical temperature, which is the product temperature above which the product melts and/or the matrix collapses. The critical temperature is determined by the operator and may be either the measured eutectic, glass transition or collapse temperature, whichever is highest in temperature. There may also be applications when some form of collapse is required. The process to efficiently remove water without losing the product matrix structure can be monitored, optimized and controlled for these applications.
From a process development perspective, cycle optimization results in a shelf temperature and chamber pressure combination that balances the heat and mass flow and maintains the product at its optimum temperature. Traditionally this is a very challenging task which involves a multi-step ‘trial and error’ approach, and is further complicated by the differing heat transfer dynamics between freeze dryers and batch sizes. This approach can result in large amounts of wasted product if multiple runs are required to achieve cycle optimization.
Heat transfer during freeze drying is a dynamic process. The total amount of heat applied to the product comes from a combination of sources including: the shelf; gas conduction; convection; radiation and inter-vial heat transfer. The proportion of the total heat from each source differs due not only to equipment and application differences, but also due to interaction between the vials.
During sublimation the shelf temperature is controlled to add heat to the product causing the ice to sublimate into vapor. Sublimation is an endothermic event, which results in a low product temperature at the sublimation front. Although the shelf may be at −15° C. the product at the bottom of the vial may be −20° C. and the temperature at the sublimation front will be at the lowest temperature, for example −35° C. When freeze drying large batches of vials, the majority of vials are surrounded by at least two outside rows of vials and there are multiple rows of vials, there is a significant amount of inter-vial cooling which slows the sublimation process. When a small batch of product is freeze dried there are a significantly larger percentage of edge vials and the inter-vial cooling effect is greatly reduced and therefore the sublimation rates are much higher.
Center vs Edge Vial—(FIGS. 1A, 1B)
A “center vial” may be defined as a single vial surrounded by at least two outside rows vials. The vast majority of vials in a larger freeze dryer are considered center vials. Center vials are exposed to minimal radiation heating and experience a cooling effect from their surrounding vials that are sublimating which results in slower freezing, lower sublimation rates, and longer drying times.
An “edge vial” can be defined as a vial that is not surrounded by two outer rows of vials. An edge vial will experience a greater amount of heat from radiation and less inter-vial heat transfer effects from surrounding vials, which results in faster freezing and faster drying times. The outer 2 to 3 rows of a tray of vials experiences an “edge effect” resulting in shorter drying times than center vials. Therefore, a small batch of vials will act more like edge vials than center vials and will therefore freeze faster and dry faster. In a 19 vial nest arranged in a hexagonal pattern (FIG. 2), the outer 2 rows are edge vials, so 18 of the 19 vials act like edge vials. A goal in freeze drying is to have the vials process uniformly for consistency and repeatability, the edge vial effect needs to be minimized to produce a consistent product.
The rate of freezing and sublimation is determined by the combined heat flow of all of the heat sources. The sources of heat flow vary between freeze dryers and batch sizes and therefore freezing and primary drying times vary. In addition, the variation in heat sources can produce differences in the dried product across the batch.
Experiments—
Table 1 (Appendix A)—To test the effect of different heat sources a series of experiments was executed. A full tray of product (12″×24″) was processed in a laboratory scale freeze dryer and the primary drying time was measured. Next 19 vials were processed in the same laboratory scale freeze dryer using the same freeze drying protocol. The 19 vials dried in 512 minutes versus 636 minutes for a full tray. The drying time for 19 vials was over 120 minutes shorter.
Based on common theory the faster drying when 19 vials are processed is caused by a larger percentage of the vials being exposed to radiation from the warm walls and door of the freeze dryer. In an effort to understand and control this variation, experiments were performed using a temperature controlled wall in a small freeze dryer. A small scale freeze dryer having a 6″ diameter shelf and a temperature controllable wall was developed. 19 vials were placed in the small freeze dryer and the sublimation uniformity and sublimation times were measured. The sublimation uniformity was measured at a point where approximately 25% of the water should have been removed. Each vial was weighed and the amount of water removed and the percentage dryness was determined. Next the temperature of the wall was reduced to −40 C to minimize radiation from the wall. Then in successive runs insulation was added around the product to shield the vials from all potential sources of radiation.
In all cases the 19 vials dried significantly faster than a full tray. Reducing the wall temperature results in reduced heat transfer from radiation sources. However, experiments with the wall temperature reduced to −40 C and with the vials insulated from any potential radiation sources resulted in a minimal change in primary drying time and minimal improvement of sublimation uniformity across the batch of vials. Therefore, reducing the temperature of the wall and implementing a radiation shield had marginal effect on the process and was not able to simulate the processing times of larger systems and larger batches of product.
Conclusion: The difference in drying times between large and small batches is not predominately a result of radiation, since minimizing radiation minimally improved the sublimation rate and uniformity across the batch. It was then hypothesized that there is a major heat transfer effect from vials being surrounded by other vials. So, another set of experiments would need to be developed to test the theory that there is a reduction in sublimation rate and better sublimation uniformity when vials are completely surrounded by other vials.
What is needed is an apparatus and method for simulating and quantifying the heat transfer dynamics created by the inter-vial heat transfer dynamics from adjacent vials in large batches, in both freezing and primary drying, when only a small batch of product is used, for example 1 to 37 vials. A method and apparatus to simulate the heat flow from adjacent vials enables the user to test the limits of operation, simulate the heat transfer dynamics of larger systems and larger batches, develop optimized freeze drying protocols, and develop transferrable protocols for a particular product.
There are many methods to transfer protocols once an optimized protocol is developed. One example of a method to transfer an optimized primary drying protocol is to determine the Thermal Conductivity of the Vial (Kv) in both the SFD an TFD, then use the Kv values to determine the TFD shelf temperature based on the SFD shelf temperature.
Example of one method to transfer the protocol from primary drying from a SFD to TFD:
      Tshelf    ⁢                  ⁢    TFD    =            (                        (                      KvSFD            KvTFD                    )                *                  (                      Tshelfsource            -            Tproductsource                    )                    )        +    Tproduct  